There have been found various proteins, called cytokines, which inhibit biological response such as immunoresponse, inflammatory reaction and hemopoietic function. As the structures and activities of cytokines have gradually been clarified, it has also been made clear that they posses a wide spectrum of immunological and nonimmunological activities and have much relevance to cell growth, differentiation, homeostasis and pathological physiology.
Among the cytokines, TNF-.alpha. has been found as an anti-tumor cytokine and has been expected to be useful as an antitumor agent. However, later on it was found that it is identical with cachectin which is a cachexy-inducing factor. It is reported that TNF-.alpha. has an activity of stimulating production of other cytokines such as IL-1, etc., proliferative activity of fibroblast, endotoxin shock-inducing activity, an activity of promoting the adhesion of leukocytes to endothelium by increasing intercellular adhesion molecules (ICAM-1, ICAM-2) or endothelial leukocyte adhesion molecule-1 (ELAM-1) [cf. Beutler, B., et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989); Akatu, K. & Suda, T., Medical Practice, 8 (9), 1393-1396 (1991)].
Moreover, it is reported that in bacterial or parasitic infectious diseases, TNF-.alpha. is contained in a higher concentration in blood and cerebrospinal fluid [cf. Mituyama, M., IGAKU-NO-AYUMI, 159 (8), 467-470 (1991); and Nakao, M., IGAKU-NO-AYUMI, 159 (8), 471-474 (1991)]. It is also reported that in rheumatoid arthritis, the joint fluid and blood serum have TNF-A activity [cf. Saxne, T., et al., Arthritis Rheum., 31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 (1991); Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990); Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); and Brennan, F. M., et al., Bri. J. Rheum., 31, 293-298 (1992)].
It is further reported that in patients suffered from a severe respiratory diseases: adult respiratory distress syndrome (ARDS), the phlegm of the patients contain an increased TNF-.alpha. [cf. Millar, A. B., et al., Nature, 324, 73 (1986)], and that TNF-.alpha. participates also in the severity of virus hepatitis [cf. Muto, Y. et al., Lancet, ii, 72-74 (1986)].
It is also reported that the blood concentration of TNF-.alpha. raises in case of myocardial ischemia (e.g. acute myocardial infarction) [cf. Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)], and it is suggested that TNF-.alpha. will participate in such diseases [cf. Lefer, A. M., et al, Science, 249, 61-64 (1990). It is recently reported that TNF-.alpha. inhibits myocardial contraction (cf. Finkel, M. S., et al., Science, 257, 387-389 (1992); and Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)].
As to Interleukin-1 (IL-1), it has been decided in the 2nd International Limphokine Workshop that the uniform designation "interleukin-1" is given to the physiologically active substance which had been called by various names such as Lymphocyte Activating Factor (LAF), Mitogenic Protein, Helper peak-1, T-cell replacing factor III (TRF-III), T-cell replacing factor macrophage (TRFM), B-cell activating factor, B-cell differentiation factor. [cf. Cellular Immunol., 48, 433-436 (1979)]. This is decided by the reason that the above physiologically active substance having various namings could not be distinguished from each other and had been designated merely based on different angles of the physiological activities.
It has been known that the above IL-1 is a biomaterial which is important for inducing and transmitting the systemic biological response against infection and inflammation, and further this substance per se has a strong antitumor activity [cf. Hirai, Y., et al.; "Gann Monograph on Cancer Research", Japan Scientific Societies Press, Tokyo (1988)], and further it has also been found that it induces response observed in the inflammation in vivo, such as fever, increase of leukocytes, activation of lymphocytes, induction of biosynthesis of acute phase protein in liver [cf. Dinarello, C. A.; Interleukin-1, Rev. Infect. Des., 6, 51-95 (1984), and Kluger, M. J., Oppenheim, J. J. & Powanda, M. C.; The Physiologic, Metabolic and Immunologic Actions of Interleukin-1, Alan R. Liss, Inc., New York (1985)].
Moreover, IL-1 has various biological activities and has been considered to be an important factor for maintaining the homeostasis, but when the function of IL-1 production is disordered and thereby IL-1 is produced in an abnormally larger amount, it may cause various diseases. For example, it has been reported that in case of rheumatoid arthritis, there is a strong correlation between the degree of inflammation of articular synovium and the degree of the bone destruction and expression of HLA-DR antigen in the synovial tissue [cf. Miyasaka, N., Sato, K., Goto, M., Sasano, M., Natsuyama, M., Inoue, K., and Nishioka, K.; Augmented Interleukin-1 Production and HLA-DR Expression in the Synovium of Rheumatoid Arthritis Patient: Arthritis Rheum., 32, (4), 476-480 (1988)].
Accordingly, it is considered that the various physiological properties associated with IL-1 may be blocked by inhibiting the excess release of IL-1 from cells. There are used glucocorticoid hormones for the treatment of chronic inflammatory diseases, and it is known that the activities will partly be due to the suppression of IL-1 production [cf. Lew, W., Oppenheim, J. J., & Matsushima, K.; Analysis of the Suppression of IL-1.alpha. and IL-1.beta. Production in Human Peripheral Blood Mononuclear Adherent Cells by a Glucocorticoid Hormone: J. Immunol., 140, (6), 1895-1902 (1988)]. However, it has been known that glucocorticoids induce disadvantageously various heavy side effects owing to its various physiological activities.
In the course of proliferation of B cells activated by antigen stimulation and the differentiation thereof into antibody-producing cells, some cytokines will act. As the cytokines participating in the proliferation there are known interleukin-4 and -5 which correspond to B cell growth factor-I and -II (BCGF-I and BCGF-II), respectively, and as the cytokines participating in the differentiation, there is known interleukin-6 (IL-6) which is B cell differentiation factor (BCDF).
The above IL-6 has firstly been found as a factor for inducing the production of immunoglobulin in B cell line transformed with EB virus in a supernatant of culture broth of peripheral blood monocytes, and thereafter it has been studied independently as various factors such as B cell stimulatory factor-2 (BSF-2), interferone-.beta.2 (IFN-.beta.2), 26 kDa protein, hepatocytes stimulatory factor, hybridoma plasmacytoma growth factor (HPGF), but it was found by Hirano et al. in 1986 that all of these cytokines are identical by cloning of them [cf. Hirano, T., et al, Nature, 324, 73 (1986)].
It has been clarified that IL-6 plays an important role in an antibody production in B cell but also is an important factor in hemopoietic system, nervous system and protective system of biobody (e.g. liver) as well as in immune system, for example, it is effective for inducing proliferation and differentiation of T cell, inducing production of protein at acute phase by acting on hepatic cells, promoting formation of pluripotential colony to the hemopoietic cells, and the like.
There are various reports concerning IL-6, its production and correlation between abnormal secretion thereof and various diseases as follows.
In various autoimmune diseases such as hypergammaglobulinemia, chronic articular rheumatism being positive in various autoantibodies, systemic lupus erythematosus, etc., polyclonal activation of B cells is induced and thereby a large amount of IL-6 is present in the joint fluid of the patients suffered from rheumatoid arthritis and IL-6 is produced by the activated T cells and B cells which are penetrated into synovium tissue [cf. Hirano, et al., Eur. J. Immunol., 18, 1797 (1988)].
It is also reported that in patients suffered from atrial myxedema having autoimmune disease-like symptom, the clinical symptom disappears by removing the tumor, from which it is assumed that the symptom will be induced by any factor produced by tumor cells. It is also suggested that IL-6 will be largely produced by these tumor cells and there is a certain correlation between the abnormal production of IL-6 and the abnormal state of polyclonal B cells [cf. Hirano, T., et al., Proc. Natl. Acad. Sci., USA, 82, 5490 (1985)].
It has already been reported that IL-6 is a factor of increasing plasmacytoma in mouse, and the increase of plasmacytoma in myeloma cells isolated from the human patient suffered from multiple myeloma could be inhibited by anti-IL-6 antibody, and therefore, it is made clear that IL-6 may probably be an autogrowth factor of myeloma cells, and thereby it is suggested that IL-6 participates largely not only in the development of the abnormal state of polyclonal B cells but also in the development of the abnormal state of monoclonal B cells such as myeloma cells [cf. Kawano, M., et al., Nature, 332, 83 (1988)].
In Castleman's disease accompanied with tumor of lymph node of which cause is unknown, high blood level of IL-6 activity is observed, and further, hypergammaglobulinemia or high level of protein in acute phase are also observed. The blood level of IL-6 becomes normal by removing the tumor of lymph node and thereby the clinical symptom is also recovered [cf. Yoshizaki, K., et al., Blood, 74, 1360 (1989)].
High IL-6 activity is observed in urine of patients suffered from primary glomerular nephritis, which activity is significantly higher than that in healty persons or in patients suffered from a minimal change nephrotic syndrome. The IL-6 activity in urine is correlative to the degree of growth of mesangial cells in tissue specimen of renal biopsy. In fact, when IL-6 is added to the culture system of rat renal mesangial cells in vitro, growth of cells is induced dependently on the concentration of IL-6, and thereby, it was made clear that IL-6 is a growth factor of mesangial cells [cf. Horii, Y., et al., J. Immunol., 143, 3949 (1989)].
Interleukin-8 (IL-8) is also called as a neutrophil activator and is a basic heparin-binding polypeptide having 72 amino acids. It is a cytokine produced by various tisse cells (not only by activated macrophage).
IL-8 is (1) a chemotactic factor to neutrophil, T cell and basophil, and has various physiological activities such as (2) activation of neutrophil and acceleration of release of lysozyme, change of adhesion of neutrophil to endothelium of blood vessel, and inhibition of growth of Candida, (3) break of the joint synovilis accompanying damping of neutrophil by injection of IL-8 into joint, (4) increase of generation of adhesion factor on neutrophil, (5) control of the histamine release in basophil, and (6) activation of neutrophil in an artificial organs. Besides, IL-8 is also called as--inflammatory cytokine, and it is considered that inflammatory diseases will be caused by abnormal production of IL-8 and excess response to IL-8.
Interferon-.gamma. (IFN-.gamma.) has firstly been reported by Wheelock in 1965 and is produced by stimulating immunocompetent cells such as T cells or natural killer cells, etc. by a specific or non-specific antigen and is rather recognized as a sort of immunomodulator than an antiviral activator [Arai, S., Akaji, A., RINSHO-MENEKI, 25 (5), 547-553 (1993)]. INF-.gamma. participates in Shwartzman reaction. (This reaction is an inflammatory reaction accompanied with bleeding and necrosis at the injected portion when a filtrated fluid of a culture of bacteria is subcutaneously injected and the same fluid is intravenously injected after about 20 hours, and when both injections of said fluid are done by intravenous route, various organs such as kidney, liver, lung, heart, etc. are damaged. This phenomenon has been found by G. Sanarelli, and hence, it is also called as "Shwartzman-Sanarelli phenomenon"). It is reported that anti-INF-.gamma. antibody inhibits said Shwartzman reaction [cf. Alfons Billian, Immunology Today, 9, 37-40 (1988)]. It is reported that in patients suffered from systemic lupus erythematosus, the concentration of INF-.gamma. in blood serum is increased, and that the concentration of INF-.gamma. is increased also in the blood serum of patients suffered from Sjogren's syndrome and polymyalgia rheumatica [cf. M. AL-Janadi, S. AL-Balla, A. AL-Dalaan, and S. Raziuddin, J. Clin. Immunol., 13, 58-67 (1993)], and further that when INF-.gamma. is injected to patients suffered from multiple sclerosis, the symptom becomes worse [cf. H. S. Panitch and C. T. Bever, Jr., J. Neuroimmunol., 46, 155-164 (1993)].
In order to treat the various diseases which may be caused by the cytokines as mentioned above, it has been considered to use a cytokine inhibitor.
By the way, the 1,4-dihydro-4-oxoquinoline-3-carboxylic acids of the formula (I) as shown hereinafter and the 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolidine-2-carboxylic acids of the formula (II) as shown hereinafter are disclosed in European Patent Publication 0287951 and U.S. Pat. No. 4,399,134 as antibacterial agents.
It is disclosed in DE-3,632,222-A that 4-oxo-quinoline-carboxylate derivatives including some compounds of the present invention are useful to treat a wide variety of diseases and infections in humans (e.g. bone and joint infections, post-operative wound infections, infections after dental operations, septic arthritis, mastitis, tonsilitis and genital and eye infections) and animals, but it does not mentioned as to the cytokine inhibiting activities.
It is disclosed in DE-3,641,312-A that 7-amino-4-oxo-quinoline-carboxylate derivatives including some compounds of the present invention are useful as antibacterials and immunostimulants, but it does not mention as to the cytokine inhibiting activities.
It is disclosed in EP-361,177-A that 6-halo-4-quinolone compounds analogous to the compounds of the present invention are useful in the treatment of rheumatoid arthritis, but it does not mention as to the cytokine inhibiting activities.
It is disclosed in DT-2,407,744 that (5-tetrazolyl)-4-quinolone-3-carboxamides analogous to the compounds of the present invention are useful for treating extrinsic asthma, hay fever, urticaria, eczema and atopic dermatitis, but it does not mention as to the cytokine inhibiting activities.
It is disclosed in GB-2,095,668 that acyl substituted quinolone-carboxylic acid derivatives analogous to the compounds of the present invention are useful as antiallergic agents, but it does not mention as to the cytokine inhibiting activities.
It is disclosed in JP-63-152,318-A that pyridone-carboxylic acid compounds analogous to the compounds of the present invention are useful as antimycoplasma agents effective against mycoplasma infectious diseases such as human penumonia or arthritis, cattle mastitis, chicken chronic diseases of the respiratory system, but it does not mention as to the cytokine inhibiting activities.
It is disclosed in DE-3,420,116-A that 1-cyclopropyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids analogous to the compounds of the present invention are useful for the treatment of immunlogical impairment due to infection, age, tumours or treatment with cytostatics, but it does not mention as to the cytokine inhibiting activities.
Furthermore, the following literatures disclose that some compounds analogous to the compounds of the present invention show IL-1 production inhibitory activity, and immune inhibitory activities:
Roche Y.; Gougerot Pocidalo M. A.; Fay M.; Etienne D.; Forest N.; and Pocidalo J. J.; J. Antimicrob. Chemother., 19 (No.6), pp. 781-790 (1987) PA0 Bailly S.; Fay M.; Roche Y.; and Gougerot Pocidalo M. A.; Int. J. Immunopharmacol., 12 (No. 1), pp. 31-36 (1990) PA0 Paton J. H.; and Reeves D. S.; Drug Safety, 6 (No. 1), pp. 8-27 (1991) PA0 Tawfik A. F.; Shoeb H. A.; Bishop S. J.; Al-Shammary F. J.; and Shibl A. M.; J. Chemother., (Florence) 1990, 2 (5), pp. 300-305 PA0 Anjo Saeko; Kondo Yuriko; Ishiboshi Yoshio; and Arai Toshihiko; J. Antimicrob. Chemother., 1992, 30 (2), pp. 240-242
It is also disclosed in the following literatures that some analogous compounds have anti-arthritis activity: Bayer, Arnold S.; Norman, Dean C.; and Anderson, Debbie; J. Infect. Dis., 1985, 152 (4), pp. 811-816, and Bayer, Arnold S.; Norman, Dean C.; Blomquist, Ingrid K.; Antimicrob. Agents Chemother. 1986, 30 (1), pp. 184-6.